# The Citric Acid Cycle Modulates Neurologic Health and Is a Therapeutic Target of Dietary and Genetic Modification in Metabolic Disease

## TL;DR

The citric acid cycle plays a key role in neurological health and could be a target for treating metabolic and neurodegenerative diseases.

## Contribution

The study reveals a new role of the citric acid cycle in maintaining circadian rhythms and neurological function.

## Key findings

- Stimulating the citric acid cycle improves neurological health in metabolic disease models.
- The CAC helps maintain normal circadian rhythms, which are linked to neurological disorders.
- GTP production by the CAC may be a key mechanism in its therapeutic potential for neurological diseases.

## Abstract

Background/Objectives: Primary metabolic diseases including mitochondrial encephalomyopathies (ME), glycolytic enzymopathies, and disorders of lipid and amino acid metabolism can manifest with severe neurological and neuromuscular symptoms. Conversely, it is increasingly appreciated that primary neurodegenerative diseases can have metabolic etiology and pathophysiology. Pharmacological treatments have limited benefit for these classes of diseases, but dietary therapy is increasingly recognized as a tool for bolstering metabolic processes that can ameliorate neurological symptoms. The ketogenic diet is the best-established example, having long been used as a therapy for epilepsy. Replenishing metabolic intermediates (anaplerosis) especially substrates of the citric acid cycle (CAC) is currently being explored, with ongoing clinical trials of simple metabolic intermediates such as oxaloacetate or NAD+ to treat neurodegenerative diseases. We have shown ketogenic and anaplerotic therapies to be effective in a Drosophila model of ME; however, the full therapeutic potential and role of the CAC in neuronal health is still not well understood. Methods: Here, we have used genetic, behavioral, and dietary approaches to elucidate critical links between the CAC and neurological function. Results: We have found that stimulating the CAC can improve and sustain neurological health in the face of severe metabolic disease, and that its functions include a previously unrecognized role in maintaining normal circadian rhythms, whose disruption is often an early indicator or complicating factor in neurological and neurodegenerative disease. We investigated the hypothesis that the production of GTP by the CAC may be an important mechanistic contributor to the role of the CAC in neurological health and disease, and may underlie its therapeutic potential. Conclusions: Overall, our findings expand our understanding of the role of the CAC in neurological health and disease, support its development as a therapeutic target, and provide a foundation for further studies investigating the intersection between neurological disease and metabolic function.